Overview
Charcot-Marie-Tooth Disease (CMT)
1. Clinical Overview
Summary
Charcot-Marie-Tooth Disease (CMT), also known as Hereditary Motor and Sensory Neuropathy (HMSN), is the Most Common Inherited Peripheral Neuropathy, affecting approximately 1 in 2,500 individuals. CMT is a group of genetically heterogeneous disorders characterised by Progressive Distal Muscle Weakness and Atrophy, Sensory Loss, Foot Deformities (Pes Cavus, Hammer Toes), and Depressed or Absent Reflexes. The name reflects the three physicians who first described it (Charcot, Marie, and Tooth in 1886). CMT is classified into Demyelinating (CMT1, CMT4) and Axonal (CMT2) types based on Nerve Conduction Studies (NCS). The most common subtype is CMT1A, caused by Duplication of the PMP22 Gene on Chromosome 17, Accounting for ~60% of demyelinating CMT. Onset is typically in the First or Second Decade of Life. Progression is slow, And most patients remain ambulatory throughout life. There is No Cure, but management focuses on Physiotherapy, Orthotics, Occupational Therapy, and Orthopaedic Surgery for severe deformities. [1,2,3]
Clinical Pearls
"Stork Legs" / "Champagne Bottle Legs": Classic description of distal lower limb wasting with preserved proximal musculature.
"Pes Cavus + Distal Weakness = Think CMT": High-arched foot is highly suggestive.
"CMT1A = PMP22 Duplication": Most common form (~50-60% of all CMT).
"Slow but Not Stopping": CMT is progressive but usually does not significantly shorten lifespan.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Prevalence | ~1 in 2,500. |
| Age of Onset | Usually First two decades. Can present later in milder forms. |
| Sex | Equal (Autosomal dominant forms). X-linked may be more severe in males. |
Genetics
| Type | Inheritance | Gene/Locus | Proportion |
|---|---|---|---|
| CMT1A | Autosomal Dominant | PMP22 Duplication (17p11.2) | ~50-60% of all CMT. |
| CMT1B | AD | MPZ (Myelin Protein Zero) | ~5%. |
| CMT1X (CMTX1) | X-Linked Dominant | GJB1 (Connexin-32) | ~10-15%. Males more severe. |
| CMT2A | AD | MFN2 (Mitofusin-2) | Most common CMT2 subtype. |
| CMT4 | Autosomal Recessive | Various | Rare. Often severe. |
| HNPP (Hereditary Neuropathy with Liability to Pressure Palsies) | AD | PMP22 Deletion | Distinct but related. Recurrent focal neuropathies. |
3. Classification
By Pathophysiology (NCS-Based)
| Type | Pathology | NCS Finding (Motor Conduction Velocity) |
|---|---|---|
| CMT1 (Demyelinating) | Primary Myelin Dysfunction | MCV less than 38 m/s (Uniformly slow). Thickened nerves (Onion bulbs). |
| CMT2 (Axonal) | Primary Axonal Degeneration | MCV >38 m/s (Normal or near-normal). Reduced amplitudes. |
| Intermediate CMT | Mixed features | MCV 25-45 m/s. |
| CMT4 | Demyelinating (Autosomal Recessive) | Severe. Early onset. |
| CMTX | Combined features | Intermediate MCV. X-Linked. |
4. Pathophysiology
CMT1 (Demyelinating)
- Genetic Defect: Mutations in genes encoding myelin proteins (PMP22, MPZ).
- Schwann Cell Dysfunction: Abnormal myelin formation and maintenance.
- Demyelination: Loss of myelin sheath.
- Remyelination Attempts: "Onion bulb" formations (Schwann cell hypertrophy around axon).
- Secondary Axonal Loss: Over time, Axons degenerate.
- Clinical Effect: Slowed nerve conduction → Weakness, Sensory loss.
CMT2 (Axonal)
- Genetic Defect: Mutations in genes affecting axonal transport, Mitochondrial function (MFN2).
- Primary Axonal Degeneration: "Dying back" neuropathy.
- Clinical Effect: Reduced muscle innervation → Weakness, Atrophy, Sensory loss.
5. Clinical Presentation
Classic Features (CMT1A – Typical)
| Feature | Notes |
|---|---|
| Onset | Childhood or Adolescence. |
| Distal Muscle Weakness | Foot dorsiflexion weakness (Foot drop). Intrinsic foot muscles. Later: Hands (Intrinsic). |
| Distal Muscle Atrophy | "Stork Legs" / "Champagne Bottle Legs" / "Inverted Champagne Bottle" (Thin calves, Preserved thighs). |
| Foot Deformities | Pes Cavus (High-arched foot). Hammer Toes. Pes Equinus. |
| Sensory Loss | Distal, "Glove and Stocking" distribution. Vibration and Proprioception often affected. Pain/Temperature may be affected. |
| Depressed / Absent Reflexes | Especially ankle jerks. Can be generalised. |
| Gait Abnormality | Steppage gait (High stepping to clear foot due to foot drop). Difficulty running. Frequent tripping/Falls. |
| Hand Weakness / Atrophy | Later involvement. Difficulty with fine motor tasks. "Claw hand" (Severe). |
| Palpably Thickened Nerves | In some (Demyelinating). Greater auricular, Superficial peroneal, Ulnar. |
| Scoliosis | Common. |
| NO Upper Motor Neuron Signs | No Babinski, No spasticity. |
| Preserved or Near-Normal Lifespan |
Symptoms
| Symptom | Notes |
|---|---|
| Tripping / Frequent Ankle Sprains | Early symptoms. |
| Difficulty Running | |
| Foot Drop | |
| Numbness / Tingling in Feet/Hands | |
| Pain | Musculoskeletal (Related to deformity). Neuropathic pain less common. |
| Hand Clumsiness | Later. |
| Fatigue |
Examination Findings
| Finding | Notes |
|---|---|
| Pes Cavus | High arch. Almost universal. |
| Hammer / Clawed Toes | |
| Distal Wasting (Legs > Arms) | |
| Weakness (Distal > Proximal) | Foot dorsiflexion/Eversion weak. |
| Steppage Gait | |
| Reduced / Absent Ankle Jerks | |
| Sensory Loss (Distal) | |
| Palpable Nerve Thickening | CMT1. |
6. Investigations
Nerve Conduction Studies (NCS) / Electromyography (EMG)
| Type | Findings |
|---|---|
| CMT1 (Demyelinating) | Uniformly Slow Motor Conduction Velocities (less than 38 m/s). Prolonged distal latencies. May have reduced amplitudes. |
| CMT2 (Axonal) | Normal or Near-Normal MCV (>38 m/s). Reduced CMAP and SNAP Amplitudes. Denervation on EMG. |
| CMTX | Intermediate MCV. May show asymmetry. |
Genetic Testing
| Notes |
|---|
| PMP22 Duplication (CMT1A): Most common. MLPA or FISH. |
| Targeted Gene Panel / Whole Exome Sequencing: If PMP22 negative or specific subtype suspected. |
| Confirms diagnosis. Essential for family counselling and future planning. |
Other Investigations
| Test | Notes |
|---|---|
| Nerve Biopsy | Rarely needed. May show onion bulbs (CMT1). Historical. |
| MRI Spine | If atypical features. Exclude other causes. |
7. Management
Management (No Cure – Symptomatic and Supportive)
CMT DIAGNOSED (Clinical + NCS + Genetic)
↓
MULTIDISCIPLINARY TEAM (MDT)
- Neurologist
- Physiotherapist (PT)
- Occupational Therapist (OT)
- Orthotist
- Orthopaedic Surgeon
- Genetic Counsellor
- Podiatrist
↓
PHYSIOTHERAPY (Core)
┌──────────────────────────────────────────────────────────┐
│ - Stretching exercises (Prevent contractures) │
│ - Strengthening (Moderate intensity – Avoid │
│ overexertion/Overwork weakness) │
│ - Balance training │
│ - Gait training │
│ - Aerobic fitness │
└──────────────────────────────────────────────────────────┘
↓
ORTHOTICS (AFO – Ankle-Foot Orthosis)
┌──────────────────────────────────────────────────────────┐
│ - For foot drop / Ankle instability │
│ - Improves gait and reduces falls │
│ - Custom moulded often needed │
│ - May need hand splints for upper limb involvement │
└──────────────────────────────────────────────────────────┘
↓
OCCUPATIONAL THERAPY
- Adaptive devices (Button hooks, Jar openers, Writing aids)
- Home and workplace modifications
- Driving assessment
↓
ORTHOPAEDIC SURGERY (Selected Cases)
┌──────────────────────────────────────────────────────────┐
│ - For fixed deformities unresponsive to conservative │
│ - Soft tissue releases (Plantar fascia, Achilles) │
│ - Tendon transfers (Tibialis posterior to foot dorsum) │
│ - Osteotomies (Midfoot, Calcaneal) │
│ - Triple Arthrodesis (Severe fixed pes cavus) │
│ - Scoliosis surgery if progressive │
└──────────────────────────────────────────────────────────┘
↓
PAIN MANAGEMENT
- Musculoskeletal pain: Physio, Orthotics, NSAIDs
- Neuropathic pain (Less common): Gabapentin, Pregabalin,
Amitriptyline
↓
GENETIC COUNSELLING
- Inheritance pattern (AD, AR, X-Linked)
- Risk to offspring/Relatives
- Prenatal testing options if desired
↓
AVOID NEUROTOXIC MEDICATIONS
- Vincristine (Chemotherapy) – Can cause severe
exacerbation
- High-dose Vitamin B6 (Pyridoxine)
- Certain antibiotics (Nitrofurantoin, Metronidazole –
Caution)
- Provide patient with "medications to avoid" list
↓
EMERGING THERAPIES (Research)
- Gene therapy (Silencing PMP22 overexpression)
- Clinical trials
8. Complications
| Complication | Notes |
|---|---|
| Falls / Injuries | Due to foot drop and sensory loss. |
| Joint Contractures | Ankle, Foot, Hand. |
| Chronic Pain | Musculoskeletal. |
| Scoliosis | |
| Respiratory Insufficiency | Rare. Seen in severe CMT4 or diaphragm involvement. |
| Severe Disability | Minority. Most remain ambulatory. |
| Vincristine Toxicity | Severe neuropathy exacerbation if given chemotherapy containing Vincristine. |
9. Prognosis and Outcomes
| Factor | Notes |
|---|---|
| Progression | Slow. Over years to decades. |
| Lifespan | Normal or near-normal. |
| Ambulation | Most patients remain ambulatory throughout life (~95%). ~5% may need wheelchair. |
| Quality of Life | Variable. Many live independently with appropriate support. |
| Variability | Even within families, Severity can vary. |
10. Evidence and Guidelines
Key Guidelines
| Guideline | Notes |
|---|---|
| CMT | AAN, CMT Association |
11. Patient and Layperson Explanation
What is Charcot-Marie-Tooth Disease?
CMT is an inherited condition that affects the nerves that control your muscles and sensation. It mainly affects the feet, Legs, Hands, And arms.
What are the symptoms?
- Weakness in the feet and legs (Difficulty lifting the front of the foot – "Foot drop").
- High-arched feet (Pes cavus).
- Hammer toes.
- Thin calves ("Stork legs").
- Numbness or tingling in the feet and hands.
- Tripping and difficulty walking.
- Later, Weakness and wasting in the hands.
What causes it?
CMT is caused by faulty genes that affect the nerves. It is usually inherited from a parent.
Is there a cure?
There is currently no cure for CMT. However, Treatment can help manage symptoms:
- Physiotherapy: Exercises to keep muscles strong and flexible.
- Orthotics: Braces or splints (AFOs) to support weak ankles and feet.
- Surgery: Sometimes needed to correct severe foot deformities.
What is the outlook?
CMT is a slowly progressive condition. Most people with CMT live normal or near-normal lifespans and remain able to walk throughout their lives.
Is there anything I should avoid?
Yes. Certain medications, Especially the chemotherapy drug Vincristine, Can severely worsen the condition. Carry a list of medications to avoid.
12. References
Primary Sources
- Reilly MM, et al. Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2011;16(1):1-14. PMID: 21504497.
- Shy ME, et al. CMT therapeutics: Opportunities and challenges. Ann Neurol. 2014;75(5):641-652.
- Pareyson D, et al. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8(7):654-667. PMID: 19539233.
13. Examination Focus
Common Exam Questions
- Most Common Subtype: "What is the most common genetic cause of Charcot-Marie-Tooth Disease?"
- Answer: CMT1A – PMP22 Duplication on Chromosome 17.
- Classic Foot Deformity: "What foot deformity is classically associated with CMT?"
- Answer: Pes Cavus (High-arched foot).
- NCS Finding (CMT1): "What is the characteristic Nerve Conduction Study finding in CMT1?"
- Answer: Uniformly Slow Motor Conduction Velocities (less than 38 m/s) (Demyelinating pattern).
- Medication to Avoid: "What chemotherapy drug should be avoided in patients with CMT?"
- Answer: Vincristine (Can cause severe neuropathy exacerbation).
Viva Points
- "Stork Legs" / "Champagne Bottle": Distal wasting with preserved proximal muscles.
- Steppage Gait: High-stepping to clear foot drop.
- Onion Bulbs on Histology: CMT1 (Demyelinating). Schwann cell hypertrophy.
- HNPP = PMP22 Deletion: Opposite of CMT1A duplication. Recurrent focal neuropathies.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.